Functionally, the basal ganglia consists of the striatum, the pallidum and the substantia nigra. These nuclei are a target of long term therapeutic regimens, such as neuroleptic treatment of psychotic patients, and are implicated in chronic neuronal dysfunctions such as Parkinson's disease, Huntington's chorea and tardive dyskinesias. Our goal is to detect changes in gene expression in neurons of the basal ganglia as a result of chronic drug injections or experimental lesions reproducing, in the mouse, these pharmacological and pathological situations. Striatal dopaminergic receptors will be blocked by repeated injections of neuroleptics, striatal efferents will be lesioned by ibotenic acid and dopaminergic neurons will be impaired by injections of 6-hydroxydopamine and N-methyl-4-phenyl 1,2,3,6 tetrahydropyridine (MPTP). In situ hybridization with radiolabelled RNA probes will be used to measure two specific messenger RNA (mRNA) at the cellular level: mRNA for glutamic acid decarboxylase (GAD) will be detected in GABA-ergic neurons of the striatum, pallidum and substantia nigra pars reticulata, and mRNA for tyrosine hydroxylase (TH) will be detected in dopaminergic neurons of the substantia nigra pars compacta. The extend, time course and exact topography of the changes in mRNA levels will be analyzed by quantitative autoradiography. When appropriate, correlations will be made with changes in mRNA levels for alpha tubulin, behavioral supersensitivity of dopaminergic receptors and neuronal metabolic activity detected by cytochrome oxidase histochemistry. Thus, we will test the hypothesis that modifications of neurotransmitter-related gene expression occurs in neurons of the basal ganglia after chronic alteration of their neuronal inputs. This study constitutes an attempt to use recently developed in situ hybridization techniques for this purpose and will provide the groundwork for future work aimed at understanding the plasticity of gene expression in the brain as a result of mutations (in diverse strains of mice), lesions, or long term pharmacological treatments similar to those commonly used in psychiatry.